19-40381069-G-A

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BP4_Strong

The NM_144685.5(HIPK4):c.922C>T(p.Arg308Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000159 in 1,612,880 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00022 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00015 (2 hom.)
• Consequence: HIPK4 NM_144685.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.473

Genes affected

HIPK4 (HGNC:19007): (homeodomain interacting protein kinase 4) This gene encodes a member of the homeodomain interacting protein kinase (HIPK) family of proteins. While other members of this family are found throughout vertebrates, this member is present only in mammals. Compared to other members of this family, the encoded protein lacks a nuclear localization signal and a C-terminal autoinhibitory domain. The encoded protein exhibits kinase activity and may phosphorylate the tumor suppressor protein p53. [provided by RefSeq, Jul 2016]

PLD3 (HGNC:17158): (phospholipase D family member 3) This gene encodes a member of the phospholipase D (PLD) family of enzymes that catalyze the hydrolysis of membrane phospholipids. The encoded protein is a single-pass type II membrane protein and contains two PLD phosphodiesterase domains. This protein influences processing of amyloid-beta precursor protein. Mutations in this gene are associated with Alzheimer disease risk. Alternatively spliced transcript variants encoding the same protein have been found for this gene. [provided by RefSeq, Apr 2014]

ACMG classification

Verdict is Likely_benign. Variant got -4 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.017347097).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HIPK4	NM_144685.5	c.922C>T	p.Arg308Trp	missense_variant	3/4	ENST00000291823.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HIPK4	ENST00000291823.3	c.922C>T	p.Arg308Trp	missense_variant	3/4	1	NM_144685.5	P1

Frequencies

GnomAD3 genomes AF: 0.000217 AC: 33 AN: 152134 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000338

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00124

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000162

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000259 AC: 64 AN: 247086 Hom.: 1 AF XY: 0.000372 AC XY: 50 AN XY: 134278

Gnomad AFR exome AF: 0.000251

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000545

Gnomad SAS exome AF: 0.00163

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000722

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000153 AC: 223 AN: 1460746 Hom.: 2 Cov.: 33 AF XY: 0.000200 AC XY: 145 AN XY: 726758

Gnomad4 AFR exome AF: 0.000299

Gnomad4 AMR exome AF: 0.0000224

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000126

Gnomad4 SAS exome AF: 0.00130

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000764

Gnomad4 OTH exome AF: 0.000166

GnomAD4 genome AF: 0.000217 AC: 33 AN: 152134 Hom.: 0 Cov.: 32 AF XY: 0.000256 AC XY: 19 AN XY: 74318

Gnomad4 AFR AF: 0.000338

Gnomad4 AMR AF: 0.000131

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00124

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000162

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000115 Hom.: 0

Bravo AF: 0.000174

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.000231 AC: 28

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.000109

EpiControl AF: 0.000119

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 26, 2021

The c.922C>T (p.R308W) alteration is located in exon 3 (coding exon 3) of the HIPK4 gene. This alteration results from a C to T substitution at nucleotide position 922, causing the arginine (R) at amino acid position 308 to be replaced by a tryptophan (W). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.092
BayesDel_addAF	Benign	-0.49	T
BayesDel_noAF	Benign	-0.50
Cadd	Benign	22
Dann	Uncertain	1.0
DEOGEN2	Benign	0.018	T
Eigen	Benign	-0.52
Eigen_PC	Benign	-0.48
FATHMM_MKL	Benign	0.32	N
LIST_S2	Benign	0.51	T
M_CAP	Benign	0.021	T
MetaRNN	Benign	0.017	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.5	L
MutationTaster	Benign	0.99	D
PrimateAI	Benign	0.41	T
PROVEAN	Benign	-1.6	N
REVEL	Benign	0.072
Sift	Uncertain	0.0050	D
Sift4G	Benign	0.090	T
Polyphen		0.42	B
Vest4		0.26
MVP		0.70
MPC		0.98
ClinPred		0.054	T
GERP RS		4.4
Varity_R		0.16
gMVP		0.53

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs139337380; hg19: chr19-40886976; COSMIC: COSV105109350; COSMIC: COSV105109350;